Abstract

BACKGROUND:

Both genetic variation at the 17q21 locus and virus-induced respiratory wheezing illnesses are associated with the development of asthma. Our aim was to determine the effects of these two factors on the risk of asthma in the Childhood Origins of Asthma (COAST) and the Copenhagen Prospective Study on Asthma in Childhood (COPSAC) birth cohorts.

METHODS:

We tested genotypes at the 17q21 locus for associations with asthma and with human rhinovirus (HRV) and respiratory syncytial virus (RSV) wheezing illnesses and tested for interactions between 17q21 genotypes and HRV and RSV wheezing illnesses with respect to the risk of asthma. Finally, we examined genotype-specific expression of 17q21 genes in unstimulated and HRV-stimulated peripheral-blood mononuclear cells (PBMCs).

RESULTS:

The 17q21 variants were associated with HRV wheezing illnesses in early life, but not with RSV wheezing illnesses. The associations of 17q21 variants with asthma were restricted to children who had had HRV wheezing illnesses, resulting in a significant interaction effect with respect to the risk of asthma. Moreover, the expression levels of ORMDL3 and of GSDMB were significantly increased in HRV-stimulated PBMCs, as compared with unstimulated PBMCs. The expression of these genes was associated with 17q21 variants in both conditions, although the increase with exposure to HRV was not genotype-specific.

CONCLUSIONS:

Variants at the 17q21 locus were associated with asthma in children who had had HRV wheezing illnesses and with expression of two genes at this locus. The expression levels of both genes increased in response to HRV stimulation, although the relative increase was not associated with the 17q21 genotypes. (Funded by the National Institutes of Health.).

Effects of 17q21 Genotype on Asthma and Human Rhinovirus (HRV) Wheezing Illnesses in the Childhood Origins of Asthma (COAST) Cohort

Panel A shows the prevalence of asthma according to 17q21 genotype, and Panel B shows the mean number of HRV wheezing illnesses in the first 3 years of life according to 17q21 genotype. Sample sizes for each genotype group are shown in parentheses under the horizontal axis. T bars in Panel B indicate standard errors. Panel C shows the prevalence of asthma among the children according to the whether they had at least one HRV wheezing illness in the first 3 years of life or no HRV wheezing illness. The dashed horizontal line shows the overall prevalence of asthma among children in the COAST cohort. P = 0.006 for the main effect of this single-nucleotide polymorphism (SNP) among children who had at least one HRV wheezing illness in the first 3 years of life, and P = 0.70 among children who did not have an HRV wheezing illness; P = 0.004 for the interaction between the rs7216389 SNP and HRV wheezing illness with respect to the development of asthma. Panel D shows the odds-ratio estimates for asthma risk associated with the three genotypes at rs7216389 among children who had at least one HRV wheezing illness in the first 3 years of life, and Panel E, the odds-ratio estimates among children who did not have any HRV wheezing illnesses in the first 3 years of life. In Panels D and E, the odds ratios are shown relative to the reference group — the children with the CC genotype who did not have any HRV wheezing illnesses. The sample size of each genotype group is shown in parentheses under the horizontal axis in both panels, and I bars indicate 95% confidence intervals.

Effects of 17q21 Genotype on Asthma and HRV Wheezing Illnesses in the Copenhagen Prospective Study on Asthma in Childhood (COPSAC) Cohort

Panel A shows the prevalence of asthma among children in the COPSAC cohort, according to whether they had at least one HRV wheezing illness in the first 3 years of life or no HRV wheezing illnesses. The dashed horizontal line shows the overall prevalence of asthma among children in the COPSAC cohort. Panel B shows the odds-ratio estimates for asthma risk associated with the three genotypes at rs7216389 among children who had at least one HRV wheezing illness in the first 3 years of life, and Panel C, the odds-ratio estimates for asthma risk associated with the three rs7216389 genotypes among children who did not have any HRV wheezing illnesses in the first 3 years of life. In both panels, the odds ratios were relative to the reference group — children with the CC genotype who did not have any HRV wheezing illnesses. In Panels B and C, the numbers in parentheses under the horizontal axis are the numbers of participants with a given genotype. I bars in Panels B and C indicate 95% confidence intervals.

Expression of IKZF3, GSDMB, and ORMDL3 in Peripheral-Blood Mononuclear Cells (PBMCs) from the Adult Participants

Relative expression levels are shown in unstimulated (U) and HRV-stimulated (HRV) PBMCs. Expression of IKZF3 was measured in 96 paired samples, and expression of GSDMB and ORMDL3 in 97 paired samples. Each circle corresponds to an individual participant. The horizontal lines show the mean expression levels. As compared with the expression of IKZF3, GSDMB, and ORMDL3 in unstimulated cells, the mean expression of these genes in HRV-stimulated cells was increased by a factor of 1.01, 1.29, and 2.17, respectively.

Association between rs7216389 Genotype and Expression of 17q21 Genes in Unstimulated and HRV-Stimulated PBMCs

Relative expression levels of IKZF3, GSDMB, and ORMDL3 are shown according to 17q21 genotype in unstimulated and HRV-stimulated PBMCs. The sample size of each genotype group is shown in parentheses under the horizontal axis. Each circle corresponds to an individual participant. The horizontal lines show the mean expression levels. The P values indicate the significance of the association between the number of T alleles and gene expression.